PROJECT SUMMARY Gammaherpesviruses establish life-long infection in a majority of humans worldwide and are associated with the development of cancer, including B cell lymphomas. The intimate relationship between gammaherpesviruses and B cell differentiation is directly linked to the lymphomagenic capacity of these viruses. To ensure the establishment of long-term latency in memory B cells, gammaherpesviruses drive a unique polyclonal germinal center reaction during early infection. Germinal center reaction represents a stage of B cell differentiation that is characterized by rapid division of activated B cells along with genetic instability driven by enzymes that either induce DNA breaks or mutagenize DNA. It is not surprising that most Epstein-Barr virus-driven B cell lymphomas originate from germinal center or post germinal center B cells. This robust, gammaherpesvirus-stimulated germinal center reaction is transient and returns to near-baseline levels in long-term infected hosts. Importantly, it is not clear what attenuates gammaherpesvirus-driven germinal center reaction. We have identified Interferon Regulatory Factor-1 (IRF-1) as the first host factor that specifically attenuates gammaherpesvirus-driven germinal center reaction. Studies proposed here test the hypothesis that IRF-1 is the critical host factor that attenuates gammaherpesvirus-driven expansion and transformation of germinal center B cells throughout life-long infection. The proposed studies will define IRF-1-mediated signaling changes that attenuate gammaherpesvirus-driven expansion of germinal center response and the relative contributions of B- and T cell-intrinsic functions of IRF-1 to this process. Further, proposed studies will develop a novel animal model of gammaherpesvirus lymphomagenesis. Successful completion of the proposed studies will offer insights into the tumor suppressor mechanisms of IRF-1 and generate novel animal models that will be of value to infectious disease, immunology, and cancer fields.